A promising strategy for reducing the public health burden of smoking-related disease, currently under consideration by the FDA's Center for Tobacco Products, is to reduce the addictiveness of tobacco by reducing the nicotine content of cigarettes to below a level that will sustain addiction. There are, however, key unanswered questions that must be addressed in order to understand the impact of such a policy on our current smoking population, who increasingly use both e-cigarettes and conventional cigarettes. What is the nicotine abuse liability threshold for tobacco cigarettes in a context where smokers use nicotine-containing e- cigarettes? What are the minimal doses of nicotine that can produce discriminable rewarding effects and engender compulsive use? Will a nicotine abuse liability threshold applicable to long-time, heavy smokers also apply to younger, lighter smokers who are more sensitive to nicotine? The proposed research will address these issues by randomizing 320 smokers (both heavy, long-time smokers and lighter, younger smokers) to switch from their usual brands of cigarettes to research cigarettes with similar tar yields but five different nicotine contents. All participants will have access to concurrent use of e-cigarettes during the 12-week exposure period. We will assess the effects of cigarette nicotine content on measures of abuse liability, including daily cigarette consumption, smoking reward and measures of dependence, such as nicotine withdrawal symptoms. In laboratory sessions, we will measure nicotine thresholds for detecting and recognizing the addictive, rewarding effects of smoking. This study is designed to help the FDA identify a target nicotine threshold that will not attract young people to smoking or induce relapse in former smokers. Additionally, we will determine the level of cigarette nicotine reduction that will be tolerated without inducing dissatisfaction in smokers, information that is relevant to the FDA for designing a stepwise nicotine reduction policy that can be implemented without widespread objections. The knowledge gained from this project will greatly increase our knowledge of nicotine addiction and will help frame an FDA policy relating to the regulation of the nicotine content of tobacco. Ultimately, a well-designed nicotine reduction policy has the potential to greatly reduce the enormous toll of death and disease caused by cigarette smoking.